Phosphorylation of RXRα mediates the effect of JNK to suppress hepatic FGF21 expression and promote metabolic syndrome.
Phosphorylation of RXRα mediates the effect of JNK to suppress hepatic FGF21 expression and promote metabolic syndrome.
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DOI：
10.1073/pnas.2210434119
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发表时间：
2022-11
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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cJUN nh2 -末端激酶（JNK）信号通路被代谢应激激活，在代谢综合征的发展过程中起关键作用。JNK2通过抑制肝因子成纤维细胞生长因子21 （FGF21）的表达在肝脏中起作用。我们发现交替剪接的JNK2α亚型介导代谢应激的影响。定量磷酸化蛋白质组学分析和基因互补分析功能检测表明，jnk2 α介导的类视黄醇X受体α (RXRα)磷酸化抑制FGF21的表达。这些观察结果确定了JNK/RXRα/FGF21信号轴有助于肥胖相关代谢综合征。肝脏中cJun nh2末端激酶（JNK）信号通路通过调节肝因子成纤维细胞生长因子21 （FGF21）的过氧化物酶体增殖物激活受体α (PPARα)依赖性表达来促进全身代谢变化。肝细胞特异性基因消融研究表明，Mapk9基因（编码JNK2）起着关键的机制作用。外显子7a和7b的互斥包含产生JNK2α和JNK2β亚型的表达。本研究表明，Fgf21基因的表达和代谢调控主要受JNK2α亚型的调控。为了鉴定JNK2α的相关底物，我们对对照小鼠、肝细胞中JNK缺乏的小鼠和肝细胞中仅表达JNK2α或JNK2β的小鼠的肝脏进行了定量磷蛋白组学研究。我们发现JNK底物类视黄醇X受体α (RXRα)在体内表现出jnk2 α促进的磷酸化。RXRα作为PPARα的异二聚体伴侣发挥作用，因此可能介导JNK2α信号传导对Fgf21表达的影响。为了验证这一假设，我们建立了肝细胞特异性表达野生型或突变RXRα蛋白的小鼠。我们发现RXRα磷酸化位点Ser260是抑制Fgf21基因表达所必需的。总之，这些数据建立了jnk介导的调节肝脏Fgf21表达的信号通路。
The cJUN NH2-terminal kinase (JNK) signaling pathway is activated by metabolic stress and plays a key role during the development of metabolic syndrome. JNK2 acts in the liver by suppressing the expression of the hepatokine fibroblast growth factor 21 (FGF21). We show that the alternatively spliced JNK2α isoform mediates the effects of metabolic stress. Quantitative phosphoproteomics analysis and functional testing using genetic complementation analysis demonstrated that JNK2α-mediated phosphorylation of retinoid X receptor α (RXRα) inhibits FGF21 expression. These observations define a JNK/RXRα/FGF21 signaling axis that contributes to obesity-associated metabolic syndrome. The cJun NH2-terminal kinase (JNK) signaling pathway in the liver promotes systemic changes in metabolism by regulating peroxisome proliferator-activated receptor α (PPARα)-dependent expression of the hepatokine fibroblast growth factor 21 (FGF21). Hepatocyte-specific gene ablation studies demonstrated that the Mapk9 gene (encoding JNK2) plays a key mechanistic role. Mutually exclusive inclusion of exons 7a and 7b yields expression of the isoforms JNK2α and JNK2β. Here we demonstrate that Fgf21 gene expression and metabolic regulation are primarily regulated by the JNK2α isoform. To identify relevant substrates of JNK2α, we performed a quantitative phosphoproteomic study of livers isolated from control mice, mice with JNK deficiency in hepatocytes, and mice that express only JNK2α or JNK2β in hepatocytes. We identified the JNK substrate retinoid X receptor α (RXRα) as a protein that exhibited JNK2α-promoted phosphorylation in vivo. RXRα functions as a heterodimeric partner of PPARα and may therefore mediate the effects of JNK2α signaling on Fgf21 expression. To test this hypothesis, we established mice with hepatocyte-specific expression of wild-type or mutated RXRα proteins. We found that the RXRα phosphorylation site Ser260 was required for suppression of Fgf21 gene expression. Collectively, these data establish a JNK-mediated signaling pathway that regulates hepatic Fgf21 expression.
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影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
64.5
作者：
Huttlin EL;Jedrychowski MP;Elias JE;Goswami T;Rad R;Beausoleil SA;Villén J;Haas W;Sowa ME;Gygi SP
通讯作者：
Gygi SP
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
4.8
作者：
Adam-Stitah, S;Penna, L;Rochette-Egly, C
通讯作者：
Rochette-Egly, C
影响因子：
29
作者：
Holland WL;Adams AC;Brozinick JT;Bui HH;Miyauchi Y;Kusminski CM;Bauer SM;Wade M;Singhal E;Cheng CC;Volk K;Kuo MS;Gordillo R;Kharitonenkov A;Scherer PE
通讯作者：
Scherer PE